The goal of this proposal is to understand the dynamics of the immune response to skin cancer induced by immunotherapy. Investigation of the immune response to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is important because these cancers are the most commonly diagnosed cancers in the US and they provide an excellent model to investigate the immune response to cancer. An understanding of tumor immunology in BCC and SCC may not only lead to non-surgical approaches for their treatment, it is likely to provide new insights into tumor immunology. The overall goal of this proposal is to understand the dynamics of the immune response to cancer induced by immunotherapy. The objectives of this proposal are to 1) Characterize the tumor infiltrating lymphocytes (TIL) of BCC and SCC according to a) phenotype including activation marker, adhesion marker and homing receptor, and b) T-cell receptor repertoire; 2) Identify the cytokines involved in the in situ response to cutaneous cancer; 3) Evaluate production of cultured TIL for cytolytic activity of BCC and SCC against tumor cells, cytokine production and T-cell receptor gene usage; and 4) Investigate the dynamics of the response to immunotherapy of BCC and SCC with IFN-alpha and IL-2 in terms of changes of predominant T-cell phenotype, T-cell receptor repertoire, in situ cytokine production and the anti-tumor cytolytic capacity of TILs. Our preliminary data indicate that immunosuppressive cytokines such as IL-10 play a role in the immune response to cutaneous tumors and that a restricted T-cell receptor repertoire exists in TIL of BCC. The answer to these questions will allow us to design specific immunologic treatments against skin cancer and will likely prove beneficial to our understanding of the role of the immune response in other cancers.